It is proposed to develop an automatic system for the large-scale synthesis of oligonucleotides including antisense oligonucleotides. Methods for oligo synthesis have been developed for small columns or fluidized beds, with each of the series of reactants necessary to add one oligonucleotide present only for short periods of time. Complete washing between steps is essential. If the reaction volume is to be scaled up from present levels (from microliters and milliliters), methods are required for rapidly changing bed volumes, for keeping interfaces between reagents sharp, for minimizing anomalous flow, for reducing the volume of reagents required per unit oligo synthesized, and for effective valving of all reagents with negligible dead volume. To avoid reagent cross-contamination a new type of computer- controlled zero-hold-up valve is also required which will allow larger numbers (more than twenty) of different fluid lines to be connected in any order to one inlet line. The basic principles required to solve scale-up problems have been worked out in theory, and the synthesis vessel built. This proposal is for completion of the valving system, for modifications of the reaction vessel, and for evaluation of flow in the total system, all in Phase I.